Photodynamic therapy (PDT) is one of therapeutic techniques to treat incurable diseases using by photosensitizer drugs having a selectivity and photoenhancing activity to cancer cells or various tumors without a surgical operation and complication occurring in chemotherapy.
The action mechanism of photosensitizer drugs is that for example, the drug is intravenously administrated to a patient and the optimum amount of light is irradiated thereto to form excited state of photosensitizer. The drugs give rise to activating oxygen molecule to transform to be excited singlet oxygen state, new radical or new chemical species resulting in attacking and demolishing cancer cells or various tumor cells selectively.
Representative photosensitizers are porphyrin compounds which have been extracted from silk worm feces or mulberry leaf or green algae and have appropriate spectrophotometric characteristics to be used as photosensitizers. Their most important characteristics are to give rise to electron transition due to infrared light whose wavelength from 700 to 900 nm allowing relative great cell penetrating activity and the production of excited state of triplet oxygen thereby.
Porphyrin derivatives as photosensitizers can selectively not only penetrate or be accumulated in tumor site but also emit fluorescence or phosphorescence and therefore, can be useful as an early stage diagnostic tool.
There have been lots of reports on several porphyrin derivatives in prior art. For example, U.S. Pat. Nos. 5,633,275; 5,654,423; 5,675,001; 5,703,230; 5,705,622 and U.S. Pat. No. 4,882,234 disclose several photofrin II compounds. It has been reported that one of those is on sale and some of those are on clinical trials now, however, those porphyrin II are the mixtures consisting of several oligomers ether-linked with haematoporphyrin (HpD).
PCT/WO 97/29915 (A) discloses BPDMA (verteporphin), a benzoporphyrin derivative, known to show specific effect on skin cancer, psoriasis and AMD. M-THPC disclosed in PCT/WO97/48393 and known to be useful in treating trachea and lung cancer or Monoaspitylchlorine disclosed in CA Registration No. 2121716 and Japanese Patent Registration No. 09071531 and known to be useful to photodynamic therapy as one of chlorine derivatives have been reported together with related several patents i.e., PCT/WO97/19081, PCT/WO 97/32885; EP 569113; U.S. Pat. Nos. 5,587,394; 5,648,485 and 5,693,632; all of which are incorporated herein by reference.
However, most of those porphyrin group compounds are meso-tetraphenylporphyrin derivatives, chlorine group, chlorophyll group, purpurine group, nerdine, Diels-Elder Reaction Adducts and so on and 5-aminolevulanic acid, phthalocyanin and the like as non-porphyrin group compounds.
Since the yield of producing singlet oxygen molecule is correlated with cell cytotoxic activity directly, the yield is in proportion with cell cytotoxic activity, which is most crucial factor together with the retention time in human body in photodynamic therapy and remains to be improved till now. However, above described clinically using porphyrin compounds as photosensitizer drugs have been reported to have several disadvantages such as too long retention time in human body delivering unfavorable photo-toxicity, which remains to be improved till now.
Accordingly, present inventors have endeavored to find novel porphyrin derivatives or their pharmaceutically acceptable salt thereof which has newly modified chlorine group improved the disadvantage of conventional photosensitizer drug i.e., physical stability, superior yield to reproduce singlet state oxygen radical and superior cell cytotoxic activity to conventional porphyrin derivatives and finally accomplished the present invention.